Commentary __________________________________________________________ ___

Value of MR in Definition of the Neuropathology of Cerebral Palsy in Vivo

Joseph J. Volpe1

Cerebral palsy refers to a clinical syndrome of nonprogressive motor deficits (usually spastic weakness, uncommonly choreoathetosis, rarely ataxia) of central origin with onset from early infancy. In this issue of the Journal, Truwit et al describe the MR findings in 40 patients with the clinical diagnosis of cerebral palsy (1). The pur­poses of their retrospective study were to define the anatomic substrates of cerebral palsy in the living patient and, from the definitions of the topography of the neuropathology and the analy­sis of clinical data, to suggest etiology and timing of the brain injury. The authors place particular emphasis on their conclusion that cerebral palsy is usually not related to perinatal factors. The work is relevant to the role of hypoxic-ischemic brain injury in the genesis of cerebral palsy, the means of diagnosis of hypoxic-ischemic brain injury in the neonatal period, the spectrum of the neuropathology associated with cerebral palsy and the role of MR in the later definition of this neuropathology, and the timing of etiologic fac­tors. These issues are discussed in sequence.

Hypoxic-Ischemic Brain Injury and Cerebral Palsy

Hypoxic-ischemic brain injury occurring either in the prenatal, perinatal, or early postnatal pe­riods may result in the motor deficits categorized as cerebral palsy (20). This brain injury is consid­ered best in the context of five basic neuropath­ologic states, ie, selective neuronal necrosis, sta­tus marmoratus of basal ganglia and thalamus, parasagittal cerebral injury, periventricular leu­komalacia, and focal and multifocal ischemic brain necrosis. Although these disorders often overlap in a given patient, the nature of the insult and the gestational age of the infant tend to cause one lesion to be dominant.

Selective Neuronal Necrosis

Selective neuronal necrosis, a common expres­sion of injury secondary to hypoxic-ischemic in­sult in the term infant, is characterized by neu­ronal destruction in a typical distribution (see ref. 2 for review). Cerebral cortical neurons, particu­larly those of the CA 1 region of hippocampus (Sommer's sector), are especially vulnerable. (In the premature infant, neuronal injury occurs prin­cipally in inferior olivary nuclei , ventral pons, and subiculum of hippocampus, although periventric­ular white matter injury tends to be the predom­inant hypoxic-ischemic lesion in such infants.) The pathophysiology of the typical neuronal in­jury of the term infant, ie, in hippocampus and neocortex, is related predominantly to the re­gional distribution of excitatory synapses me­diated by the excitotoxic amino acid glutamate (see refs. 3-6 for reviews). Hypoxic-ischemic in­sults lead to a combination of increased release from nerve endings and decreased uptake by presynaptic neurons and by astrocytes and, con­sequently, to the toxic accumulation of extracel­lular glutamate. Glutamate-induced injury occurs by rapid and delayed mechanisms. The latter may be the more important, is calcium-mediated, and probably generates ultimately toxic free radicals. Current studies suggest that therapy with either glutamate receptor blockers, calcium channel blockers, or free radical scavengers could be of major benefit. Regional metabolic factors related to energy metabolism, calcium homeostasis, and free radical scavenging capabilities, may play contributory pathogenetic roles in the determi­nation of the topography of selective neuronal injury, but more data are needed on these issues. Regional circulatory factors also may play a con­tributory pathogenetic role, since the cortical neu­ronal injury tends to be worse in arterial border zones and end zones in the depths of sulci and

1 Neurologist-in-Chief and Bronson Crothers Professor of Neurology, Department of Neurology, Children's Hospital and Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115. Address reprint requests to J . J . Volpe.

Index terms: Cerebral palsy; Commentaries

AJNR 13:79-83, Jan/ Feb 1992 0195-6108/ 92/ 1301 -0079 © American Society of Neuroradiology

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in the parasagittal regions of cerebral cortex. The subsequent motor correlate of selective neu­ronal injury is usually quadriparesis, spastic or hypotonic.

Status fvfarmoratus of Basal Ganglia and Thalamus

Status marmoratus of basal ganglia and thala­mus, an unusual form of selective injury, involves neuronal injury, gliosis, and hypermyelination in caudate, putamen, globus pallidus, and thalamus (2) . The pathophysiology is related principally to two major factors: the transient maturation-de­pendent dense concentration of glutamate recep­tors in basal ganglia of perinatal human brain (7) and the vulnerability of neurons undergoing ac­tive differentiation in the perinatal period. Circu­latory factors may contribute. The subsequent motor correlate is choreoathetosis.

Parasagittal Cerebra/Injury

Parasagittal cerebral injury, the principal is­chemic lesion of the term infant, is characterized by cerebral cortical and subcortical injury in a characteristic superomedial distribution, bilateral, with the posterior cerebrum affected more than anterior (2). Pathophysiology is based on the presence of characteristic arterial border zones and end zones in the parasagittal regions. These zones are particularly vulnerable to a fall in cere­bral blood flow, which is especially likely to occur in the newborn with systemic hypotension during and after perinatal asphyxia because of an ac­companying pressure-passive cerebral circulation (8). The latter lack of autoregulation occurs in the asphyxiated newborn because of several in­terrelated factors. The subsequent motor corre­late is spastic quadriparesis, with the proximal limbs affected more than distal and the upper extremities more than lower extremities.

Periventricular Leukomalacia

Periventricular leukomalacia, the principal is­chemic lesion of the premature infant, is charac­terized by necrosis of periventricular white mat­ter, dorsal and lateral to the external angle of the lateral ventricle (2) . Although more common in the premature infant, periventricular leukomala­cia is by no means rare in the term infant sub­jected to ischemic insult. The pathophysiology is related to the occurrence of periventricular arte-

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rial border zones and end zones, a pressure­passive state of the cerebral circulation, the rela­tively limited vasodilatory capability of the blood vessels in peri ventricular white matter, relatively active anaerobic glycolysis in periventricular white matter, and the intrinsic vulnerability of actively differentiating periventricular glial cells (9). The increasing recognition of more diffuse injury to periventricular white matter in small premature infants (10, 11), out of the bounds of presumed arterial border zones and end zones, emphasizes the possibility that the intrinsic met­abolic properties of periventricular white matter may be as important as the vascular factors. The subsequent motor correlate of periventricular leu­komalacia is spastic diplegia, a kind of spastic quadriparesis in which lower extremities are af­fected much more than upper extremities.

Focal and /Vfultifocallschemic Brain Necrosis

Focal and multifocal ischemic brain necrosis is characterized by injury to all cellular elements (ie, an infarction) in a vascular distribution (2). Single or multiple vessels, arteries or veins, may be involved. The distribution of the middle cerebral artery is the single most common vascular terri­tory affected. The pathophysiology is multifac­torial. Obstructions of vessels by vascular malde­velopment, vasculopathy, embolus and thrombus have been documented. By mechanisms not yet clear, apparent generalized circulatory insuffi­ciency in the perinatal period also may be fol­lowed by focal or multifocal cerebral ischemic lesions. The subsequent motor correlates consist of spastic hemiparesis or spastic quadriparesis.

Diagnosis of Hypoxic-Ischemic Brain Injury in the Neonatal Period

The diagnosis of the five lesions described above in the living infant has been based primarily on brain imaging, ie, cranial ultrasonography (US), computed tomography (CT), and recently, magnetic resonance (MR), and on neurophysio­logic techniques. Selective neuronal necrosis cur­rently is assessed most commonly by neurophys­iologic techniques, especially electroencephalog­raphy (EEG), but also brain stem auditory evoked responses and visual evoked responses. Such EEG patterns as burst-suppression or persistent and pronounced voltage suppression are indica­tive of serious cortical neuronal injury (2). How­ever, less severe degrees of neuronal injury are

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not defined clearly by neurophysiologic tech­niques. Moreover, in our experience, brain imag­ing modalities have not been highly useful in the neonatal period in identification of cortical neu­ronal injury, except in its most severe form. However, experience with MR in this setting still is relatively limited. (The later cortical atrophy, which correlates with neuronal loss and gliosis, of course is detected readily by CT and MR.)

Injury to basal ganglia and thalamus is detected best by MR. Thus, Keeney et al (12) showed that MR detected hypoxic-ischemic basal ganglia in­jury in five infants, whereas US identified abnor­mality in four of the five infants and CT in only one of the three studied by this modality.

Parasagittal cerebral injury has been identified most readily by radionuclide brain scanning (2, 13) or positron emission tomography (2, 14), only uncommonly by CT (15), and never, in our ex­perience, with US. However, the recent demon­stration of neonatal parasagittal cerebral injury by MR (12, 16) suggests that this lesion now may be detectable with this modality and, of course, with superior localization to radionuclide scanning.

Periventricular leukomalacia is identified most readily in the newborn by cranial US (see ref. 9 for review). Bilateral periventricular echogenic areas, especially in the peritrigonal regions, in the first week, correlate with necrosis accompanied by vascular congestion and/ or hemorrhage; echolucent foci, after 1 to 3 weeks in the same distribution, correlate with formation of periven­tricular cysts; ventricular enlargement, often with disappearance of cysts after 3 months or more, correlates with diminished myelin deposition and collapse of cysts with gliosis. MR also is particu­larly useful in the identification of periventricular white matter injury in the neonatal period (12), and in subsequent months and years, the ap­pearance of increased signal on T2-weighted im­ages in the periventricular white matter is a par­ticularly prominent indicator of old periventricular leukomalacia ( 17).

Focal and multifocal ischemic brain necrosis generally is effectively identified by CT (except in the first day or two after the insult), although the recent data of Keeney et al suggest that MR may prove to be superior ( 12). Acute focal cere­bral ischemic lesions also are identifiable as ech­ogenic lesions by US, although smaller and more peripherally placed infarcts, eg, in posterior pari­etal regions, may be missed by US.

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Spectrum of Neuropathology Associated with Cerebral Palsy as Defined by Later MR

The study of Truwit et al (1) provides important information regarding the spectrum of neuropath­ology associated with cerebral palsy in patients between 1 month and 41 years of age and the value of MR in defining that spectrum. Their first observation of particular interest is that MR de­tected an abnormality of brain in 93% of their patients with cerebral palsy (1). This is a remark­able yield for any modality in such a heteroge­neous group of patients.

The neuropathology defined in the premature infants consisted of a diminution in periventricular white matter in every patient (1). Moreover, the findings were consistently suggestive of periven­tricular leukomalacia. Thus, the topography of the white matter involvement usually was peritri­gonal and/ or accompanied by prolongation of T2 relaxation. Interestingly, three patients also had small brain stems, perhaps in part because of the pontine and olivary neuronal necrosis referred to earlier. In nine of the 11 infants, the perinatal course was characterized by clinical circum­stances suggestive of fetal or neonatal hypoxic­ischemic insults, usually neonatal. No develop­mental abnormalities of brain were noted in the premature infants. Thus, these data suggest that cerebral palsy in the premature infant is related to periventricular myelinoclastic disease, occur­ring most often in the postnatal period, and is rarely related to underlying developmental brain abnormality.

The spectrum of neuropathology defined in the term infants with cerebral palsy differed clearly from that in the premature infants. Thus, 31 % of the 29 term infants exhibited evidence for neu­ronal migrational disturbance (1). The largest pro­portion (59%) had an apparently heterogeneous collection of abnormalities that included particu­larly diminished cerebral myelin, with cortical thinning and/or cerebral infarction and/or hydra­nencephaly and/ or multicystic encephalomacia and/or basal ganglia and thalamic lesions. Only 10% had no definable abnormality. The relatively high proportion of disturbances of neuronal mi­gration included particularly focal cerebral corti­cal disturbances with an "abnormally thick" cor­tical mantle, characterized by Truwit et a! (1) as "polymicrogyria" (eight of nine cases), and a sin­gle case of schizencephaly. Of the 59% with the heterogeneous collection of abnormalities, appar­ent cerebral cortical atrophy (thinning of cerebral cortex) was present in three cases and abnormal

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signal intensities in basal ganglia and thalamus in six cases. We consider these two groups the probable correlates of selective cerebral cortical neuronal injury and basal ganglia/thalamus injury as described earlier. The abnormalities in white matter are more difficult to characterize. Thus, 19 term infants exhibited diminution of myelin, but in only eight cases were long T2 signals observed, and in only nine cases was the dimi­nution of myelin peritrigonal (1). These findings suggest that only approximately 50% of the in­fants with myelin abnormality had periventricular leukomalacia. The remaining approximately 50% of cases with diminished myelin did not have features highly suggestive of periventricular leu­komalacia and appeared to require other expla­nations for the myelin diminution. Such expla­nations would include a developmental defect of myelin formation, perhaps analogous to that re­corded in neuropathologic studies by Richardson and coworkers (18), or a secondary disturbance of myelin deposition because of impaired axonal formation . The impaired axonal formation could be present either as a consequence of neuronal migrational disturbance (six of the 19 infants with diminution of myelin had evidence for neuronal migrational defect as defined above), an intrinsic derangement of neuronal outgrowth, ie, a so­called organizational event of brain development (2), or prior neuronal injury with subsequently stunted axonal development.

Timing of Lesions Responsible for Cerebral Palsy in Term Infants

The timing of the abnormalities in the term infants with cerebral palsy relates to the nature of the pathologies. Thus, the neuronal migrational disturbances must originate during the peak time period for migrational events in the human cere­bral cortex, ie, 3 to 5 months of gestation. The nature of the focal cerebral cortical disturbance described by Truwit et al (1) as polymicrogyria was characterized by a thick cortical mantle, a finding which is compatible with pachygyria as well as with polymicrogyria . If the latter, the disturbance would be expected to originate in approximately the fifth month of gestation; if the former, the disturbance would be expected to originate in the fourth month of gestation (2). The timing of the apparent selective neuronal injury involving cerebral cortex or basal ganglia and thalamus is unclear. In several patients, perinatal hypoxic-ischemic insults appear to have been

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responsible, although the retrospective nature of the study precludes more refined definition of timing. The timing of the disturbance of cerebral myelin that appears to be related to periventric­ular leukomalacia is unclear, ie, an ischemic insult either in the third trimester of pregnancy or in the perinatal period could produce the abnormal­ity. A developmental disturbance of neuronal development with secondary impairment of mye­lination could have its onset from the latter months of gestation to approximately the first year of postnatal life. Similarly, a developmental disturbance of cerebral myelination per se pre­sumably would have its onset around the time of birth.

Truwit et al considered that 5 of the 29 term infants ( 17%) had MR and perinatal historical data suggestive of "perinatal" hypoxic-ischemic injury ( 1 ). Two additional infants (7%) had data suggestive of both prenatal and perinatal injury. Despite the problems of attempting to draw con­clusions about timing from a retrospective study, this value (ie, 17%-24%) is similar to that ob­tained in several large-scale epidemiologic studies of patients with cerebral palsy. Thus, studies in recent years from Sweden, Finland, the United States, Australia, and Ireland suggest a perinatal origin of cerebral palsy in approximately 12%-24% of cases who were term infants (19-26). Although Truwit et al (1) emphasized that "only 24% exhibited perinatal brain injury, it should be recognized that, because of the relatively high prevalence of cerebral palsy, this 24% represents a large absolute number of infants. Moreover, although current methods of fetal monitoring have not led to a marked decrease in the number of infants with cerebral palsy secondary to peri­natal events, it remains entirely reasonable to suspect that perinatal causes of cerebral palsy ultimately should be preventable to a large de­gree. Clearly, newer methods of fetal monitoring and definition of exact timing and mechanisms of perinatal brain injury are needed.

Conclusions

This most interesting study by Truwit et al (1) shows that cerebral palsy in the premature infant is related primarily to periventricular white matter injury, perhaps occurring primarily in the neonatal period. Cerebral palsy in the term infant has a more heterogeneous basis; ischemic injury to cerebral cortex, basal ganglia and thalamus, and to myelin accounts for some, but by no means

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all, cases. Timing is perinatal in approximately 17%-24% of such cases. Strikingly, cerebral cortical dysgenesis secondary to disordered neu­ronal migration appears to account for nearly one-third of cerebral palsy in term infants. MR is of major value in identification of the anatomic substrates for cerebral palsy.

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